ABSTRACT Sepsis is a life-threatening condition commonly encountered in intensive care settings. While advancements in clinical sepsis management have lowered acute sepsis mortality rates, a growing number of severe sepsis survivors progress to chronic illness states. Indeed, many survivors report persistent muscle weakness, breathing difficulties, and cognitive decline as debilitating complications in their post-sepsis life. We hypothesize that a key to managing the long-term effect of sepsis is to understand how sepsis-associated circulating factors impact the metabolic state of long-lived, tissue specific stem cells. Given the high incidence of post-sepsis muscle dysfunction, we propose to initially evaluate acute and persistent metabolic defects in skeletal muscle stem cells. In adult skeletal muscle, satellite cells are the primary resident stem cell population and are indispensible contributors to skeletal muscle repair and regeneration. Since establishing my independent laboratory, we have made significant progress towards understanding how wasting-associated factors impair satellite/muscle stem cell (SC) biology and we are well positioned to explore the mechanistic and metabolic basis of muscle dysfunction following septic shock. The big picture question proposed in this MIRA/R35 application is: How do sepsis-associated factors impact SC function? This proposal highlights three of our developing project areas that address this central question using distinct experimental and conceptual tactics. First, we will explore how sepsis-associated cytokines modulate SC metabolism. We found that muscle wasting/cachexia-associated cytokines can augment pathways involved in regulating energetic metabolism and propose to define the effects of sepsis-associated cytokine exposure on lipid metabolism in SCs. Second, we will examine the mechanisms by which sepsis-associated metabolites impact SC function. We present evidence that wasting-associated metabolites can antagonize stem cell differentiation and propose investigating the hypothesis that some of these sepsis metabolic biomarkers also function as bioactive signaling molecules capable of augmenting SC activation. Third, we will leverage cutting edge metabolomics analyses of muscle stem cells isolated from murine sepsis models to define metabolic signatures associated with sepsis onset and extended recovery. We show that SCs can exhibit sustained metabolic alterations to acute metabolic disruptions and propose that sepsis-associated metabolic derangements compromise SC metabolic networks long into the recovery period. These three proposed project areas are supported by rigorous past training in stem cell biology, a vibrant research and clinical environment at the Mayo Clinic, and continued professional support and guidance from experienced faculty mentors. Overall, successful completion of this proposed MIRA/R35 award will: a) facilitate the establishment of a dynamic, independent, and cost- efficient NIGMS-focused junior faculty research program at the Mayo Clinic, b) advance our understanding of how stem cells respond and adapt to sepsis-associated factors, and c) drive the field of long-term sepsis management into new and underexplored areas, such as stem cell manipulation and metabolic reprogramming.